This project is designed to test a central hypothesis that silencing the master immune negative regulator MSK (mitogen- and stress-activated protein kinase) in dendritic cells will allow them to be fully activated by MSLN-VLP stimulation, significantly increasing the active immune response and eliminating the suppressive immune response. This would increase the therapeutic efficiency of the DC vaccine against pancreatic cancer in the mouse model. Two specific aims are proposed: 1) To determine critical roles of MSKs in DC antigen presentation, cytokine production, and T cell stimulation in vitro. We hypothesize that blocking the MSK1 and MSK2 genes in DCs will enhance DC activation and the Ag-presentation property;it will also reduce immune suppressive cytokine production, and reduce Treg production. 2) To determine the active immune response induction and therapeutic efficacy of DC vaccine with MSK silencing and MSLN-VLP stimulation in the mouse models of pancreatic cancer. We hypothesize that DC vaccine with MSK silencing and MSLN-VLP stimulation could induce stronger active immune responses and efficiently control pancreatic cancer progression in the orthotopic implant pancreatic cancer mouse model. Overall, we expect these studies to contribute significantly to our knowledge of pancreatic cancer vaccine development with immediate implications in therapeutic treatment of human pancreatic cancer. PUBLIC HEALTH RELEVANCE: The incidence of pancreatic cancer remains equal to the mortality rate, new approaches to the treatment of pancreatic cancer are urgently needed. This project is designed to develop a novel virus-like particle (VLP) stimulated dendritic cell (DC) immunotherapeutic vaccine for pancreatic cancer. By blocking the immune inhibitory factors in DC, this vaccine may have an enhanced ability to process tumor antigens and generate tumor-specific response biased immunity, thereby enhancing the efficacy of VLP immunotherapy against pancreatic cancer.